Catalytic Asymmetric Cycloadditions between Aldehydes and

Note Cite This: J. Org. Chem. 2018, 83, 15499−15511

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Catalytic Asymmetric Cycloadditions between Aldehydes and Enolizable Anhydrides: cis-Selective Dihydroisocoumarin Formation Maria Luisa Aiello, Umar Farid, Cristina Trujillo, Brendan Twamley, and Stephen J. Connon* Trinity Biomedical Sciences Institute, School of Chemistry, The University of Dublin, Trinity College, Dublin 2, Ireland

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S Supporting Information *

ABSTRACT: In the presence of a trityl-substituted cinchona alkaloid-based catalyst, homophthalic, aryl succinic, and glutaconic anhydride derivatives reacted with aromatic and aliphatic aldehydes to produce cis-lactones in up to 90:10 dr and 99% ee. A DFT study has shown how the catalyst is uniquely able to bring about the opposite sense of diastereocontrol to that usually observed.

T

give a cis-diastereomer, and (c) the presence of the styrenyl unit make the development of a direct, broad-scope catalytic approach to cis-dihydroisocoumarins (especially in view of recent interest in these species following the isolation of the eurotuimide family of antifouling and antibacterial natural products17) an attractive goal. Herein, we report the first such methodology involving the efficient cis-selective asymmetric cycloaddition of enolizable anhydrides and both aromatic and aliphatic aldehydes using a trityl-substituted squaramide catalyst, which controls the stereocenter forming event in an unusual and unexpected fashion. Our study began with a catalyst screen (Table 1). As substrates, we chose the aliphatic hydrocinnamaldehyde 14 and homophthalic anhydride 1 under the conditions used in previous studies (0.1 M, MTBE, −15 °C). Crude reaction mixtures were esterified in situ to prevent retro-cycloaddition and facilitate analysis of the resulting esters by CSP-HPLC. The prototype (thio)urea-based cinchona alkaloid catalyst systems 16 and 1718 promoted the reaction with poor-tomoderate enantio- and diastereocontrol, favoring the transstereoisomer 15a (entries 1 and 2). Sulfonamide-substituted analogues (18−20, entries 3−5), regardless of their steric/ electronic characteristics, fared little better, although their use did provide 15b in higher (albeit unsatisfactory) ee than 15a. Attention therefore returned to the squaramide-substituted alkaloid family of catalysts utilized in the original study. Specifically, we varied the steric demand of the N-alkyl (i.e. nonalkaloid-bound) substituent as much as possible to probe

he reaction between enolizable cyclic anhydrides and aldehydes to form carboxy lactones is over a century old;1−5 however, a catalytic asymmetric variant of the process was not reported until 2012.6 Since then, the family of electrophiles amenable to these enantioselective reactions with anhydrides has been extended to include activated ketones,7 Michael acceptors,8 and imines.9 In the first such asymmetric reaction, homophthalic anhydride (1) was shown, in the presence of a bifunctional squaramide-based cinchona alkaloid catalyst 3,10 to undergo cycloaddition with a range of aldehydes 2 to form trans-3,4dihydroisocourmain (a structural unit present in numerous natural and synthetic molecules of medicinal and biological importance11) products of general type 4a and b with excellent enantiocontrol and good-to-excellent diastereoselectivity favoring the formation of the trans-stereoisomer (Figure 1A). A short time later, α-aryl succinic anhydrides 5 were reported to participate; providing access to arylated analogues of transparaconic acids 6a and b with similar efficiency and stereochemical outcomes.12,13 Calculations indicate that these reactions involve the catalyst deprotonating the anhydride and organizing the face-selective encounter between the squaramide-bound enolate and the ammonium ion-bound aldehyde in the stereocenter-forming step (i.e. 7, Figure 1A).14 In 2011, Yeung and coworkers15 reported an enantioselective approach to the synthesis of trans-3,4-dihydroisocoumarins such as 9a via an elegant bromocyclization of a styrenyl carboxylic acid 8 promoted by thiocarbamate substituted cinchona alkaloid-derived catalyst 10 in excellent ee. These can be elaborated to cis-derivatives via SN2 substitution. The competing formation of 9b16 and the requirements for (a) very low temperatures, (b) onward manipulation of the product to © 2018 American Chemical Society

Received: September 24, 2018 Published: November 21, 2018 15499

DOI: 10.1021/acs.joc.8b02332 J. Org. Chem. 2018, 83, 15499−15511

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The Journal of Organic Chemistry Table 1. Catalyst Evaluation

Figure 1. Organocatalytic formation of dihydroisocoumarins.

its influence on diasterocontrol. The 3,5-bis(trifluoromethyl)phenyl substituted materials 21 and 22 performed as expected: leading to the generation of both 15a and 15b in excellent ee but with 2:1 or 3:1 product ratios, respectively, favoring the undesired 15a. Interestingly, 21, which is devoid of the C-2 phenyl unit at the catalyst’s quinoline moiety, promoted the formation of greater levels of 15a than its substituted variant 15b, and so this (often beneficial) structural modification was not considered in all subsequent catalyst designs.19 Analogues of 21 in which the squaramide’s aromatic ring has been exchanged for a benzyl- (i.e. 23), D-, or L-phenylglycinepyrrolidinamide (i.e. 24 and 25) or triethylmethyl (i.e. 26) substituent failed to perturb the levels of transdiastereocontrol to an appreciable extent (entries 8−11). While the incorporation of a very large tricyclohexylmethyl (i.e. 27) group led to the formation of a greater proportion of 15b, enantioselectivity was poor (entry 12). The hindered C-2 symmetric catalyst 28 also catalyzed the cycloaddition slowly with ca. 1:1 dr, but this reaction provided almost racemic 15b (entry 13). Gratifyingly, the use of the N-trityl catalyst 29 led to a remarkable reversal of the trend, affording predominantly the cis-15b in 90% ee with the minor trans-diastereomer also formed with excellent enantiocontrol (entry 14). Extending the reach of the trityl group through the installation of p-methyl moieties did not lead to further improvement (entry 15). A subsequent solvent and temperature screen identified THF as a superior medium, allowing the formation of 15b with 71:29 dr and 99% ee (Table 1 entry 16). With a catalyst and conditions leading to diastereo- and highly enantioselective formation of cis-dihydroisocoumarins in hand, we next evaluated the substrate scope. A range of aliphatic aldehydes were evaluated as substrates for the process (Table 2). Lactones derived from straight chain (i.e. products 31 and 32), β-branched (i.e. product 33, XRD structure shown in inset), and α-branched (i.e., 34−37) aldehydes could be

entry

cat.

T (h)

yield (%)a

15a:15ba

ee15a (%)b

ee15b (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16d

16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 29

120 120 180 168 144 48 24 96 144 144 48 120 192 33 48 48

79 91 84 65 60 99 94 82 52 74 89 94 50 97 85 99

54:46 60:40 55:45 58:42 66:34 67:33 75:25 76:24 80:20 65:35 71:29 52:48 56:44 28:72 24:76 29:71

20 60 42 10 18 99 90 94 92 76 92 12 51 91 0 92

0 0 47 47 51 99 98 70 16 14 34 5 3 90 80 99

a

Combined yield of both diastereomers determined by 1H NMR spectroscopy using 4-iodoanisole as an internal standard. bDetermined by 1H NMR spectroscopy. cDetermined by CSP-HPLC. dTHF solvent.

efficiently synthesized with good-to-high cis-diastereocontrol and excellent-to-outstanding levels of enantiomeric excess, with the latter class of substrate providing products with ≥80:20 dr and 98−99% ee. Cinnamaldehyde proved a more difficult substrate from a diastereocontrol standpoint, yet 38 was still formed with high ee. Use of aldehydes incorporating nonconjugated olefin (i.e., product 39) and Michael acceptor functionality were welltolerated by the catalyst: no competing Tamura cycloaddition8 chemistry was observed during the formation of 40. The only disappointing result occurred when an aldehyde incorporating a H-bond donating Boc-protected amine was utilized: in this 15500


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The Journal of Organic Chemistry Table 2. Substrate Scope: Aliphatic Aldehydesa

in all cases involving a wide variety of functionalities. Esterified cycloadducts stemming from electron-neutral (i.e. 42), electron-deficient (i.e. 43−47), electron-rich (i.e. 48), hindered (i.e., 49), and heterocyclic (i.e. 50 and 51) aromatic aldehydes were isolated with moderate diastereocontrol and good-excellent ee. The process is not restricted to homophthalic anhydride (1). A bromo-derivative (52, Scheme 1) could be reacted with the Scheme 1. Use of Bromohomophthalic Anhydride

branched aldehyde 53 to yield cis-54 in high dr and 98% ee. Gratifyingly, other enolizable anhydrides were also compatible: use of the p-nitrophenyl succinic anhydride 55 in the presence of 53 provided 50% yield of the very sterically congested lactone 56 with similar stereocontrol (Scheme 2). a

Scheme 2. Use of an Enolizable Succinic Anhydride

case, compound 41 was formed with a considerably lower ee of 81%. Aromatic aldehydes were substrates which were shown earlier to be exceptionally well-suited to the trans-selective cycloaddition reaction.6 As expected, these were more difficult to coax into forming cis-dihydroisocoumarins (Table 3); however, catalyst 29 still promoted cis-selective cycloaddition

A glutaconic anhydride derivative 5712 was also utilized (Scheme 3). This reacted with 53 to generate the densely

Yield refers to combined isolated yield of both diastereomers. Diastereomeric ratios determined by 1H NMR spectroscopy. Enantiomeric excess determined by CSP-HPLC

Scheme 3. Use of a Glutaconic Anhydride Derivative

Table 3. Substrate Scope: Aromatic Aldehydesa

functionalized, highly malleable cis-ester derivative 58 in moderate isolated yield but excellent ee. This is the first time this anhydride class has been shown to react with aldehydes in an enantioselective process. Likewise, employment of α,αdiphenyl aldehyde 59 provided the corresponding lactone 60 in high isolated yield and 98% ee. This reaction was noteworthy in that the parent acid was formed as a single diastereomer; however, a dr of 90:10 cis:trans was observed after esterification, despite careful experimentation and very mild conditions. This was not observed in any other case.20 To rationalize both the stereochemical outcome of the process and the key contribution of the catalyst’s trityl unit, we carried out density functional theory (DFT) calculations on the reaction between 1 and 53 catalyzed by 29 (Figure 2). These were revealing: the catalyst deprotonates and binds the anhydride, directing the same face of the enolate toward the ammonium ion-bound aldehyde as seen before (i.e. 7); however, it does so in a very distinct fashion, via binding of the neutral (as drawn) carbonyl oxygen atom with the squaramide group. Further insight into this curious binding

a

Yield refers to isolated yield of the cis-diastereomers. Diastereomeric ratios determined by 1H NMR spectroscopy. Enantiomeric excess determined by CSP-HPLC. 15501


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The Journal of Organic Chemistry

Procedure for the Synthesis of Catalyst 29. Synthesized according to the literature procedure as a white solid (3.85 g, 91%).13 Mp 156−158 °C, 1H NMR (400 MHz, DMSO-d6): δ = 8.61 (d, J = 4.5 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.56−7.46 (bs, 1H), 7.38 (dd, J = 2.3, 9.2 Hz, 1H), 7.20−7.09 (m, 9H), 7.07−6.91 (m, 6H), 6.55 (bs, 1H), 6.39 (bs, 1H), 5.91−5.71 (m, 2H), 5.06−4.96 (m, 2H), 3.90 (s, 3H), 3.69 (bs, 1H), 3.34−3.12 (m, 2H), 2.67−2.46 (m, 3H), 2.31− 2.21 (m, 1H), 1.70−1.58 (m, 1H), 1.55−1.40 (m, 3H), 0.74−0.57 (m, 1H). Procedure for the Synthesis of Compound 1.6 A 50 mL round-bottomed flask containing a magnetic stirring bar was charged with homophthalic acid (2.00 g, 11.1 mmol). Acetic anhydride (25 mL) was added, the flask was fitted with a condenser and the reaction mixture was heated at 80 °C for 2 h. The excess acetic anhydride was removed in vacuo and the solid obtained was triturated with Et2O (10 mL), filtered and dried to obtain homophthalic anhydride (1) as an off-white solid (1.50 g, 85%). Mp 141−142 °C (lit.,21 mp 143−144 °C); 1H NMR (400 MHz, DMSO-d6): δ = 8.05 (d, J = 7.9 Hz, 1H), 7.75 (app. t, 1H), 7.52 (app. t, 1H), 7.44 (d, J = 7.8 Hz, 1H), 4.28 (s, 2H). (E)-Ethyl-7-oxohept-2-enoate (S1). Synthesized according to the procedure developed by Singleton et al.22 To an aqueous solution of glutaraldehyde (15 mL, 166 mmol, 25% w/v in water) in CH2Cl2 (3 mL) was added a solution of (carboethoxymethylene)triphenylphosphorane (5.78 g, 16.6 mmol) in CH2Cl2 (5 mL). The corresponding reaction mixture was allowed to stir at room temperature for 12 h, after which time EtOAc (30 mL) was added. The resulting solution was washed with water (20 mL) and then concentrated under reduced pressure. The crude product obtained was then purified by flash column chromatography eluting with 80:20 hexanes:EtOAc to furnish (E)-S1 as a colorless oil (1.24 g, 44%). 1H NMR (400 MHz, CDCl3): δ 9.79−9.74 (t, J = 1.3 Hz, 1H), 6.93 (dt, J = 6.8, 15.7 Hz, 1H), 5.85 (d, J = 15.7 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.50 (dt, J = 1.3, 13.2 Hz, 2H), 2.33−2.21 (m, 2H), 1.89−1.77 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H); HRMS (ESI) m/z: [M − H]− Calcd for C9H13O3169.0867; Found 169.0865. tert-Butyl (2-Aminoethyl)carbamate (S2). Synthesized according to the procedure developed by Guenter et al.23 A 500 mL roundbottomed flask containing a magnetic stirring bar was charged with a solution of ethylenediamine (5.6 mL, 83.3 mmol) in CH2Cl2(25 mL). A solution of di-tert-butyl dicarbonate (3.05 g, 14.0 mmol) in CH2Cl2(200 mL) was then added dropwise over 3 h. The volatiles were removed in vacuo, and the resulting oil was dissolved in a saturated aqueous solution of Na2CO3 (300 mL) and extracted with CH2Cl2 (2 × 150 mL). The combined organic phases were dried over anhydrous MgSO4 and concentrated under reduced pressure to afford S2 as colorless oil (1.59 g, 71%). 1H NMR (400 MHz, CDCl3): δ 4.90 (bs, 1H), 3.13 (m, 2H), 2.76 (m, 2H), 1.41 (s, 9H), 1.22 (bs, 2H); HRMS (APCI) m/z: [M + H]+ Calcd for C7H17N2O2 161.1284; Found 161.1289. tert-Butyl (3-Oxopropyl)carbamate (S3). Synthesized according to the procedure developed by Fujisawa et al.24 An oven-dried 50 mL round-bottomed flask containing a magnetic stirring bar under an argon atmosphere was charged with a solution of DMSO (3 mL, 32.3 mmol) in CH2Cl2 (57 mL), followed by oxalyl chloride (1.4 mL, 16.1 mmol) at −78 °C. The resultant mixture was stirred for 15 min, and a solution of S2(1.71 g, 10.7 mmol) in CH2Cl2 (50 mL) was added dropwise. After 1 h, triethylamine (7.5 mL, 53.8 mmol) was added at −78 °C, and the corresponding solution was allowed to stir at room temperature for 30 min. The reaction mixture was then quenched with a 10% aqueous solution of HCl (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with a saturated aqueous solution of NaHCO3, then brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography eluting with 70:30 hexanes:EtOAc, to afford S3 as a yellow oil (1.50 g, 81%). TLC (hexanes:EtOAc 8:2, v/v): Rf = 0.42; 1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 4.73 (bs, 1H), 3.48−3.32 (m, 2H), 3.75− 3.60 (m, 2H), 1.42 (s, 9H); HRMS (APCI) m/z: [M + Na]+ Calcd for C8H15NO3Na 196.0944; Found 196.0936.

Figure 2. DFT-based stereochemical insight.

mode was provided by QTAIM theory (Figure 2, right). The unexpected binding mode is stabilized by attractive interactions between the catalyst’s o- and m-trityl protons and two of the enolate’s oxygen atoms, thereby explaining why the trityl-substituted catalyst alone was capable of bringing about the formation of predominantly cis-products (for further discussion, see the Supporting Information). This gave us a salutary lesson regarding simplistic thinking in catalyst design: what was intended to be a repulsive steric interaction in fact influenced enolate binding by attractive means. In conclusion, we developed the first enantioselective cycloaddition reaction between aldehydes and enolizable anhydrides, which is cis-selective. Diastereocontrol up to 90:10 dr and enantiomeric excesses up to 99% are possible. The process is of broad scope: aliphatic aldehydes are superior substrates to aromatic analogues; however, both are accepted by the catalyst. Homophthalic, aryl succinic, and glutaconic anhydride derivatives are also compatible. DFT calculations have shown that the unique ability of 29 is due in part to an ability of the trityl aromatic protons to undergo attractive interactions with the catalyst-bound anhydride conjugate base.

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EXPERIMENTAL SECTION

General Information. 1H NMR spectra were recorded on Bruker DPX 400 MHz spectrometer using CDCl3, DMSO-d6, or D2O as solvents and referenced relative to residual CHCl3(δ 7.26 ppm) DMSO (δ 2.50 ppm) or H2O (δ 4.79 ppm). Chemical shifts are reported in ppm and coupling constants (J) in Hertz. 13C NMR spectra were recorded on the same instruments (100 MHz) with total proton decoupling. Fluorine NMR spectra were recorded on the Bruker DPX400 machine (376.5 and 202 MHz respectively). HSQC, HMBC, NOE, and ROESY NMR experiments were used to aid assignment of NMR peaks when required. All melting points are uncorrected. Infrared spectra were obtained using neat samples on a PerkinElmer Spectrum 100 FT-IR spectrometer equipped with a universal ATR sampling accessory. ESI mass spectra were acquired using a Waters Micromass LCT time-of-flight mass spectrometer (TOF), interfaced to a Waters 2690 HPLC. APCI experiments were carried out on a Bruker microTOF-Q III spectrometer interfaced to a Dionex UltiMate 3000 LC or direct insertion probe. The instrument was operated in positive or negative mode as required. Flash chromatography was carried out using silica gel, particle size 0.04− 0.063 mm. TLC analysis was performed on precoated 60F254 slides and visualized by UV irradiation or KMnO4 staining. Optical rotation measurements were made on a Rudolph Research Analytical Autopol IV instrument and are quoted in units of 10−1 deg cm2 g−1. Anhydrous THF, CH2Cl2, and Et2O were obtained by using Pure Solv MD4EN Solvent Purification System. Methanol (MeOH) was dried over activated 3 Å molecular sieves. Commercially available anhydrous tbutyl methyl ether (MTBE), 1,4-dioxane, 2-methyltetrahydrofuran (2MeTHF), 1,2-dimethoxyethane, and diisopropyl ether were used. Analytical CSP-HPLC was performed on Daicel Chiralpak, AD, ADH, IA, OD, OD-H, OJ-H (4.6 mm × 25 cm) and using ACQUITY UPC2, Trefoil CEL1, CEL2, 2.5 μm (3.0 × 150 mm). 15502


Note


syringe. The reaction was allowed to stir for 20 min at −15 °C, after which time the solvent was removed in vacuo. The resultant crude mixture of diastereomeric esters was then purified by flash column chromatography to furnish both diastereomers. General Procedure D for the Enantioselective Synthesis of Kavalactones (Scheme 3). An oven-dried 10 mL round-bottomed flask containing a magnetic stirring bar under an argon atmosphere was charged with phenyl glutaconic anhydride (57, 46.3 mg, 0.246 mmol), catalyst 29 (8.13 mg, 0.0123 mmol to 5 mol %) and anhydrous THF (0.1 M). The resulting mixture was cooled to −15 °C, and the relevant aldehyde (1 equiv) was added via syringe. The reaction was allowed to stir at −15 °C and for a time indicated in Scheme 3. The yield and diastereomeric ratio of the carboxylic acids were determined by 1H NMR spectroscopic analysis using piodoanisole (0.5 equiv) as an internal standard. The reaction was then diluted with EtOAc (10 mL) and extracted with a 10% aqueous solution of NaHCO3 (15 mL). The combined aqueous phases were acidified with an aqueous solution of HCl (2.0 N, 5 mL), and the mixture was then extracted with EtOAc (3 × 15 mL). The combined organic extracts were dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to furnish the diastereomeric mixture of carboxylic acids. To a solution of the corresponding carboxylic acids in dry THF (0.1 M) cooled to −15 °C, anhydrous iPrOH (94 μL, 1.23 mmol), followed by trimethylsilyldiazomethane (2.0 M solution in diethyl ether, 150 μL, 0.300 mmol) were added via syringe, and the reaction mixture was allowed to stir for 20 min. The solvent was then evaporated under reduced pressure, and the crude mixture of diastereomeric esters was purified by flash column chromatography to furnish both diastereomers. The enantiomeric excesses of the products were determined by CSP-HPLC using the conditions indicated for each case. Methyl-1-oxo-3-((E)-styryl)isochromane-4-carboxylate (15a, 15b). Prepared according to general procedure B, using freshly distilled hydrocinnamaldehyde (14, 32.0 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 33 h to give a diastereomeric mixture of carboxylic acids in a 71:29 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 80:20 hexanes:EtOAc, cis-15b and trans-15a were isolated combined as a pale yellow oil (74.0 mg, 99%). CSP-HPLC analysis: Chiralcel OJ-H (4.6 mm × 25 cm), hexane/IPA: 70/30, 0.3 mL min−1, RT, UV detection at 254 nm, retention times: cis-15b 70.4 min (major enantiomer) and 105.9 min (minor enantiomer); trans-15a 60.6 min (major enantiomer) and 79.2 min (minor enantiomer). Spectral data for this compound were consistent with those in the literature.6 TLC (hexanes/EtOAc, 8:2 v/ v): Rf = 0.34; cis-15b: 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 7.9 Hz, 1H), 7.56 (app. t, 1H), 7.48 (app. t, 1H), 7.32−7.24 (m, 2H), 7.25−7.14 (m, 4H), 4.60−4.52 (m, 1H), 3.83 (d, J = 3.2 Hz, 1H), 3.67 (s, 3H), 3.05−2.90 (m, 1H), 2.90−2.83 (m, 1H), 2.31−2.18 (m, 1H), 2.14−2.02 (m, 1H); trans-15a: 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 7.7 Hz, 1H), 7.57 (app. t, 1H), 7.47 (app. t, 1H), 7.32− 7.24 (m, 3H), 7.25−7.14 (m, 3H), 4.90−4.82 (m, 1H), 3.92 (d, J = 6.8 Hz, 1H), 3.76 (s, 3H), 3.05−2.90 (m, 1H), 2.83−2.75 (m, 1H), 2.15−2.01 (m, 1H), 1.99−1.84 (m, 1H); HRMS (APCI) m/z: [M + H]+ Calcd for C19H19O4 311.1277; Found 311.1284. Methyl-3-heptyl-1-oxoisochromane-4-carboxylate (cis-31, trans-31). Prepared according to general procedure B, using freshly distilled octanal (38.4 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 18 h to give a diastereomeric mixture of carboxylic acids in a 76:24 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 90:10 hexanes:EtOAc, cis-31 and trans-31 were isolated combined as a white solid (70.4 mg, 94%). CSP-HPLC analysis: Chiralcel IA (4.6 mm × 25 cm), hexane/IPA: 98/2, 0.5 mL min−1, RT, UV detection at 221 nm, retention times: cis-31 48.4 min (minor enantiomer) and 62.1 min (major enantiomer); trans-31 33.4 min (minor enantiomer) and 35.6 min (major enantiomer). Mp 50−55 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.61; [α]20D = −3.2 (c = 0.05, CHCl3); *cis-31: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.8 Hz, 1H), 7.61 (app. t, 1H), 7.50 (app. t, 1H), 7.32 (d, J = 7.4 Hz,

Bromoisochroman-1,3-dione (52). Synthesized according to the literature procedure as an off-white solid (800 mg, 85%).25 Mp 176− 177 °C (lit.,25 171−173 °C); 1H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 2.0, 8.3 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 4.23 (s, 2H). 3-(4-Nitrophenyl)dihydrofuran-2,5-dione (55). Synthesized according to the literature procedure as a white solid (1.20 g, 68%).12 Mp 66−68 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 4.84 (dd, J = 8.3, 10.2 Hz, 1H), 3.44 (dd, J = 10.2, 18.3 Hz, 1H), 3.32 (dd, J = 8.3, 18.3 Hz, 1H). Phenyl-2H-pyran-2,6(3H)-dione (57). Synthesized according to the literature procedure as a white solid (118 mg, 51%).8 Mp 195− 197 °C (lit.,8 mp 193−195 °C); 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, J = 6.7 Hz, 2H), 7.55−7.41 (m, 3H), 6.78 (s, 1H), 4.15 (s, 2H). General Procedure A for the Racemic Synthesis of Dihydroisocoumarins and γ-Butyrolactones (Table 1 Entry 16, Tables 2 and 3). An oven-dried 10 mL round-bottomed flask containing a magnetic stirring bar under an argon atmosphere was charged with the relevant anhydride (1 equiv) and anhydrous THF (2.5 mL, 0.1 M). The relevant aldehyde (1 equiv) followed by N,Ndiisopropylethylamine (8.6 μL, 0.0492 mmol, 20 mol %) were then added via syringe, and the resulting mixture was allowed to stir for 20 h at room temperature. To the corresponding solution of carboxylic acids in THF (2.5 mL, 0.1 M), were added via syringe anhydrous MeOH (750 μL, 18.5 mmol), followed by trimethylsilyldiazomethane (2.0 M solution in diethyl ether, 150 μL, 0.300 mmol) and the reaction was allowed to stir for 30 min at room temperature. The solvent was then removed in vacuo, and the crude mixture of diastereomeric esters was purified by flash column chromatography to afford both diastereomers. General Procedure B for the Enantioselective Synthesis of Dihydroisocoumarins and γ-Butyrolactones (Table 1 Entry 16, Tables 2 and 3). An oven-dried 10 mL round-bottomed flask containing a magnetic stirring bar under an argon atmosphere was charged with the relevant anhydride (1.0 equiv), catalyst 29 (8.13 mg, 0.0123 mmol, 5 mol %) and anhydrous THF (0.1 M). The resulting mixture was cooled to −15 °C, and the relevant aldehyde (1 equiv) was added via syringe. The reaction was allowed to stir at −15 °C and for a time indicated in Table 1 entry 16, Tables 2 and 3, Scheme 1 and 2. The yield and diastereomeric ratio of the carboxylic acids were determined by 1H NMR spectroscopic analysis using p-iodoanisole (0.5 equiv) as an internal standard. The reaction was then diluted with EtOAc (10 mL) and extracted with a 10% aqueous solution of NaHCO3 (15 mL). The combined aqueous phases were acidified with an aqueous solution of HCl (2.0 N, 5 mL), and the mixture was then extracted with EtOAc (3 × 15 mL). The combined organic extracts were dried over anhydrous MgSO4 and the solvent was removed under reduced pressure to furnish the diastereomeric mixture of carboxylic acids. To a solution of the carboxylic acid products in dry THF (0.1 M) were added via syringe anhydrous MeOH (750 μL, 18.5 mmol) followed by trimethylsilyldiazomethane (2.0 M solution in diethyl ether, 150 μL, 0.300 mmol), and the reaction was allowed to stir for 20 min. The solvent was then evaporated in vacuo, and the crude mixture of diastereomeric esters was purified by flash column chromatography to isolate both diastereomers, the enantiomeric excesses of which were determined by CSP-HPLC. General Procedure C for the Racemic Synthesis of Kavalactones Derivatives (Scheme 3). An oven-dried 10 mL round-bottomed flask containing a magnetic stirring bar under an argon atmosphere was charged with phenyl glutaconic anhydride (57, 46.3 mg, 0.246 mmol) and anhydrous THF (2.5 mL, 0.1 M). The relevant aldehyde (1 equiv) was then added to the reaction followed by equal amounts of catalyst 18 (14.2 mg, 0.0246 mmol, 10 mol %) and its pseudoenantiomer catalyst epi-18 (14.2 mg, 0.0246 mmol, 10 mol %) and the resulting mixture was allowed to stir for 20 h at room temperature. The corresponding solution of carboxylic acids in dry THF (2.5 mL, 0.1 M) was then cooled to −15 °C and anhydrous iPrOH (94 μL, 1.23 mmol), followed by trimethylsilyldiazomethane (2.0 M solution in diethyl ether, 150 μL, 0.300 mmol) were added via 15503


Note


6.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.7, 163.8, 135.8, 134.1, 130.4, 128.7, 127.4, 124.7, 77.4, 52.8, 48.8, 42.8, 24.2, 23.1, 21.5; IR (neat): 2956, 1719, 1605, 1459, 1311, 1264, 1163, 1113, 1087, 993, 948, 827, 711, 606, 567; HRMS (APCI) m/z: [M + H]+ Calcd for C15H19O4 263.1277; Found 263.1273. Asterisk (*) refers to cis-33 which was isolated after trituration of the diastereomeric mixture with isopropanol. Methyl-3-isopropyl-1-oxoisochromane-4-carboxylate (cis-34, trans-34). Prepared according to general procedure B, using freshly distilled isobutyraldehyde (22.4 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 18 h to give a diastereomeric mixture of carboxylic acids in a 84:16 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 85:15 hexanes:EtAOc, cis-34 and trans34 were isolated combined as a white solid (54.9 mg, 90%). CSPHPLC analysis: Chiralcel ODH (4.6 mm × 25 cm), n-hexane/IPA: 85/15, 0.5 mL min−1, RT, UV detection at 221 nm, retention times: cis-34 20.3 (minor enantiomer) and 21.8 min (major enantiomer); trans-34 15.2 min (major enantiomer) and 17.2 (minor enantiomer). Mp 69−72 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.26; [α]20D = −5.1 (c = 0.05, CHCl3); * cis-34: 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 7.5 Hz, 1H), 7.56 (app. t, 1H), 7.50 (app. t, 1H), 7.31 (d, J = 7.5 Hz, 1H), 4.15 (dd, J = 3.0, 9.9 Hz, 1H), 4.01 (d, J = 3.0 Hz, 1H), 3.65 (s, 3H), 2.13−2.03 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H); 13C{1H} (100 MHz, CDCl3): 169.4, 164.9, 137.1, 133.7, 130.7, 129.0, 127.3, 125.6, 84.4, 52.6, 46.2, 31.1, 18.5, 19.4; trans-34: 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 7.8 Hz, 1H), 7.58 (app. t, 1H), 7.48 (app. t, 1H), 7.21 (d, J = 7.4 Hz, 1H), 4.64−4.60 (m, 1H), 4.04 (d, J = 6.4 Hz, 1H), 3.77 (s, 3H), 1.88−1.77 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.5, 165.6, 136.1, 134.1, 130.3, 128.6, 127.3, 125.6, 83.9, 52.8, 46.3, 30.9, 19.3, 17.2; IR (neat): 2973, 1718, 1604, 1436, 1263, 1210, 1168, 1109, 1084, 983, 768, 714, 642; HRMS (APCI) m/z: [M + H]+ Calcd for C14H17O4 249.1121; Found 249.1122. Asterisk (*) refers to a mixture of cis-34:trans-34 in a 84:16 ratio. Methyl-1-oxo-3-(pentan-3-yl)isochromane-4-carboxylate (cis35, trans-35). Prepared according to general procedure B, using freshly distilled 2-ethylbutyraldehyde (30.3 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 6 days to give a diastereomeric mixture of carboxylic acids in a 88:12 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 95:5 hexanes:EtOAc, cis-35 and trans-35 were isolated combined as a white solid (61.2 mg, 90%). CSP-HPLC analysis: ACQUITY UPC2, Trefoil AMY1, 2.5 μm (3.0 × 150 mm). ABPR: 1500 (psi). A (CO2) = 97%/B (Ethanol/ACN/IPA 1:1:1, v:v:v) = 3%, 1.2 mL min−1, 30 °C, UV detection at 254 nm, retention times: cis-35 2.05 min; trans-35 2.02 min. Mp 45−47 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.64; [α]20D = −3.9 (c = 0.04, CHCl3); * cis-35: 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 7.7 Hz, 1H), 7.58 (app. t, 1H), 7.50 (app. t, 1H), 7.34 (d, J = 7.7 Hz, 1H), 4.45 (dd, J = 2.9, 9.8 Hz, 1H), 4.01 (d, J = 2.9 Hz, 1H), 3.68 (s, 3H), 1.90−1.77 (m, 3H), 1.70−1.59 (m, 1H), 1.55−1.42 (m, 1H), 0.94− 0.88 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.5, 165.0, 137.2, 133.6, 130.7, 129.0, 127.3, 125.6, 80.6, 52.6, 46.1, 41.7, 20.0, 19.7, 9.8, 9.6; trans-35: 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 5.8 Hz, 1H), 7.61 (app. t, 1H), 7.50 (app. t, 1H), 7.23 (d, J = 7.6 Hz, 1H), 4.90−4.84 (m, 1H), 4.14 (d, J = 6.7 Hz, 1H), 3.80 (s, 3H), 1.90−1.77 (m, 3H), 1.70−1.59 (m, 1H), 1.55−1.42 (m, 1H), 0.94− 0.88 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.9, 164.2, 137.2, 134.0, 130.4, 128.6, 127.2, 125.6, 80.7, 52.7, 46.2, 43.2, 21.9, 20.9, 11.2, 10.8; IR (neat): 2963, 2878, 1724, 1604, 1458, 1264,1226, 1158, 1110, 1085, 997, 717, 691; HRMS (ESI) m/z: [M + Na]+ Calcd for C16H20O4Na 299.1259; Found 299.1279. Asterisk (*) refers to a mixture of cis-35:trans-35 in a 90:10 ratio. Methyl-3-cyclohexyl-1-oxoisochroman-4-carboxylate (cis-36, trans-36). Prepared according to general procedure B, using freshly distilled cyclohexanecarboxyaldehyde (29.8 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 24 h to give a diastereomeric mixture of carboxylic acids in

1H), 4.63−4.59 (m, 1H), 3.88 (d, J = 3.2 Hz, 1H), 3.69 (s, 3H), 1.92−1.82 (m, 1H), 1.84−1.73 (m, 1H), 1.66−1.61 (m, 1H), 1.52− 1.47 (m, 1H), 1.47−1.32 (m, 8H), 0.92−0.86 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.3, 164.8, 136.8, 133.7, 130.7, 129.0, 127.2, 125.5, 78.7, 52.6, 47.9, 32.8, 31.73, 29.2, 29.04, 25.2, 22.7, 14.1; trans-31: 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 8.0 Hz, 1H), 7.58 (app. t, 1H), 7.48 (app. t, 1H), 7.23 (d, J = 7.4 Hz, 1H), 4.63 (ddd, J = 3.8, 6.5, 12.5 Hz, 1H), 3.92 (d, J = 6.5 Hz, 1H), 3.81 (s, 3H), 1.83−1.74 (m, 1H), 1.66−1.61 (m, 2H), 1.52−1.47 (m, 1H), 1.47−1.32 (m, 8H), 0.92−0.86 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.7, 163.9, 135.9, 134.0, 130.5, 128.6, 127.3, 124.7, 79.1, 52.7, 48.4, 33.7, 31.7, 29.1, 29.08, 25.0, 22.6, 14.0; IR (neat): 3133, 3025, 1730, 1680, 1580, 1467, 1156, 1125, 1096, 1012, 790, 685, 705; HRMS (APCI) m/z: [M + H]+ Calcd for C18H25O4 305.1747; Found 305.1760. Asterisk (*) refers to a mixture of cis-31:trans-31 in a 79:21 ratio. Methyl-3-benzyl-1-oxoisochromane-4-carboxylate (cis-32, trans-32). Prepared according to general procedure B, using freshly distilled phenylacetaldehyde (27.4 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 48 h to furnish a diastereomeric mixture of carboxylic acids in a 87:13 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 80:20 hexanes:EtOAc, cis-32 and trans-32 were isolated combined as a white solid (67.1 mg, 92%). CSP-HPLC analysis: Chiralcel IA (4.6 mm × 25 cm), n-hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: cis-32 40.3 min (minor enantiomer) and 48.0 min (major enantiomer); trans-32 15.4 min (major enantiomer) and 21.6 min (minor enantiomer). Mp 68−70 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.41; [α]20D = −4.5 (c = 0.04, CHCl3); *cis-32: 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 6.5 Hz, 1H), 7.56 (app. t, 1H), 7.49 (app. t, 1H), 7.45−7.36 (m, 5H), 7.35 (d, J = 6.9 Hz, 1H), 4.81 (ddd, J = 2.9, 6.7, 7.8 Hz, 1H), 3.84 (d, J = 2.9 Hz, 1H), 3.73 (s, 3H), 3.30 (dd, J = 6.7, 14.2 Hz, 1H), 3.16 (dd, J = 7.8, 14.2 Hz, 1H);13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 164.6, 136.7, 135.8, 133.7, 130.7, 129.5, 129.1, 128.8, 127.4, 127.2, 125.4, 79.7, 52.7, 46.7, 38.9; trans32: 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 6.4 Hz, 1H), 7.64 (app. t, 1H), 7.49 (app. t, 1H), 7.45−7.36 (m, 5H), 7.17 (d, J = 6.3 Hz, 1H), 5.22−5.17 (m, 1H), 3.86 (d, J = 5.2 Hz, 1H), 3.72 (s, 3H), 3.17 (dd, J = 6.3, 14.1 Hz, 1H), 2.89 (dd, J = 7.8, 14.1 Hz, 1H);13C{1H} NMR (100 MHz, CDCl3): δ 170.4, 163.5, 135.5, 135.2, 134.3, 130.5, 129.5, 128.87, 128.82, 127.9, 127.3, 124.7, 79.4, 52.8, 46.5, 39.6; IR (neat): 3030, 2952, 1724, 1658, 1453, 1434, 1376, 1261, 1158, 1119, 1030, 979, 738, 698; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H16O4Na 319.0940; Found 319.0945. Asterisk (*) refers to a mixture of cis-32:trans-32 in a 84:16 ratio. Methyl-3-isopropyl-1-oxoisochromane-4-carboxylate (cis-33, trans-33). Prepared according to general procedure B, using freshly distilled isovaleraldehyde (26.9 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 18 h to give a diastereomeric mixture of carboxylic acids in a 78:22 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 80:20 hexanes:EtOAc, cis-33 and trans33 were isolated combined as a white solid (58.7 mg, 91%). CSPHPLC analysis: Chiralcel ODH (4.6 mm × 25 cm), n-hexane/IPA: 95/5, 1.0 mL min−1, RT, UV detection at 221 nm, retention times: cis-3316.8 min; trans-3311.2 min. Mp 95−97 °C; TLC (hexanes/ EtOAc, 8:2 v/v): Rf = 0.27; [α]20D = −6.3 (c = 0.04, CHCl3); * cis33: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.8 Hz, 1H), 7.59 (app. t, 1H), 7.51 (app. t, 1H), 7.33 (d, J = 7.4 Hz, 1H), 4.72 (ddd, J = 3.3, 4.5, 9.2 Hz, 1H), 3.83 (d, J = 3.3 Hz, 1H), 3.70 (s, 3H), 2.10− 2.01 (m, 1H), 1.88 (ddd, J = 5.9, 9.2, 14.6 Hz, 1H), 1.58 (ddd, J = 4.5, 8.4, 14.6 Hz, 1H), 1.01 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H);13C{1H} NMR (100 MHz, CDCl3): 169.3, 164.8, 136.8, 133.7, 130.7, 129.0, 127.2, 125.4, 76.8, 52.6, 48.3, 41.5, 24.1, 22.9, 21.9; trans-33: 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 7.4 Hz, 1H), 7.63−7.59 (m, 1H), 7.49−7.45 (m, 1H), 7.24 (d, J = 7.3 Hz, 1H), 4.96 (ddd, J = 4.5, 6.1, 9.2 Hz, 1H), 3.87 (d, J = 6.1 Hz, 1H,), 3.80 (s, 3H), 2.01−1.94 (m, 1H), 1.85 (ddd, J = 5.9, 9.2, 14.6 Hz, 1H), 1.55 (ddd, J = 4.5, 8.4, 14.6 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 15504


Note

The Journal of Organic Chemistry a 80:20 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 90:10 hexanes:EtOAc, cis-36 and trans-36 were isolated combined as a pale yellow oil (67.4 mg, 95%). Spectral data for this compound were consistent with those in the literature.6 CSP-HPLC analysis: Chiralcel ODH (4.6 mm × 25 cm), n-hexane/IPA: 60/40, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: cis-36 59.5 min (minor enantiomer) and 65.1 min (major enantiomer); trans-36 51.8 min(major enantiomer) and 62.3 min (minor enantiomer). cis-36: 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 7.6 Hz, 1H), 7.58 (app. t, 1H), 7.50 (app. t, 1H), 7.33 (d, J = 7.6 Hz, 1H), 4.26 (dd, J = 3.0, 9.9 Hz, 1H), 4.03 (d, J = 3.0 Hz, 1H), 3.69 (s, 3H), 2.41−2.23 (m, 1H), 2.03−1.08 (m, 8H), 1.08− 0.95 (m, 2H); trans-36: 1H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 7.9 Hz, 1H), 7.58 (app. t, 1H), 7.46 (app. t, 1H), 7.22 (d, J = 7.6 Hz, 1H), 4.66 (m, 1H), 4.06 (d, J = 5.7 Hz, 1H), 3.77 (s, 3H), 1.97−1.88 (m, 1H), 1.87−1.08 (m, 10H); HRMS (APCI) m/z: [M − H]− Calcd for C17H19O4 287.1288; Found 287.1277. (3R,4R)-Methyl-3-benzhydryl-1-oxoisochromane-4-carboxylate (cis-37, trans-37). Prepared according to general procedure B, using freshly distilled diphenylacetaldehyde (43.6 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 48 h to give a diastereomeric mixture of carboxylic acids in a 87:13 ratio (cis:trans). After esterification, the crude mixture was purified by flash column chromatography to give 37 (a chromatographically inseparable mixture of diastereomers with retention of dr) as a white solid (78.1 mg, 85%). Full characterization of cis-37 was made possible by trituration of the diastereomeric mixture with IPA in which trans-37 is completely soluble. Full characterization of trans-37 was complicated due to the partial solubility of cis-37 in IPA.CSPHPLC analysis: ACQUITY UPC2, Trefoil AMY1, 2.5 μm (3.0 × 150 mm). ABPR: 1500 (psi). A (CO2) = 97%/B (Ethanol/ACN/IPA 1:1:1, v:v:v) = 3%, 1.2 mL min−1, 30 °C, UV detection at 254 nm, cis37 3.38 min (minor enantiomer) and 3.58 min (major enantiomer); trans-37 3.69 min(major enantiomer) and 3.85 min (minor enantiomer). Mp 174−176. °C; TLC (hexanes:EtOAc, 8/2 v/v): Rf = 0.67; [α]20D = −2.9 (c = 0.04, CHCl3); * cis-37: 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 7.7 Hz, 1H), 7.56 (app. t, 1H), 7.50 (app. t, 1H), 7.43−7.38 (m, 2H), 7.38−7.25 (m, 8H), 7.22 (t, J = 7.3 Hz, 1H,), 5.39 (dd, J = 2.4, 10.9 Hz, 1H), 4.59 (d, J = 10.9 Hz, 1H), 3.75 (d, J = 2.4 Hz, 1H), 3.66 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.9, 164.4, 140.2, 140.1, 136.9, 133.7, 130.7, 129.1, 129.0, 128.6 (C × 2), 128.1, 127.6, 127.5, 126.8, 125.3, 79.9, 53.6, 52.4, 45.8; IR (neat): 3029, 1734, 1724, 1600, 1494, 1452, 1251, 1221, 1157, 1107, 1085, 996, 973, 749, 695, 592; HRMS (APCI) m/ z: [M + H]+ Calcd for C24H21O4373.1434; Found 373.1434. Asterisk (*) refers to cis-37 which was isolated after trituration of the diastereomeric mixture with isopropanol. Methyl-1-oxo-3-((E)-styryl)isochromane-4-carboxylate (cis-38, trans-38). Prepared according to general procedure B, using freshly distilled cinnamaldehyde (31.0 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 18 h to give a diastereomeric mixture of carboxylic acids in a 63:37 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 80:20 hexanes:EtOAc, cis-38 and trans38 were isolated combined as a pale yellow oil (57.6 mg, 76%). CSPHPLC analysis: ACQUITY UPC2, Trefoil AMY1, 2.5 μm (3.0 × 150 mm). ABPR: 1500 (psi). A (CO2) = 97%/B (Ethanol/ACN/IPA 1:1:1, v:v:v) = 3%, 1.2 mL min−1, 30 °C, UV detection at 254 nm, retention times: cis-38 3.0 min (minor enantiomer) and 3.3 min (major enantiomer); trans-38 3.4 min (major enantiomer) and 3.7 min (minor enantiomer). TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.42; [α]20D = −6.0 (c = 0.03, CHCl3); *cis-38: 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 7.7 Hz, 1H,), 7.63 (app. t, 1H), 7.54 (app. t, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.42−7.29 (m, 4H), 6.91 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 6.1, 16.0 Hz, 1H), 5.36 (ddd, J = 1.4, 3.5, 6.1 Hz, 1H,), 4.08 (d, J = 3.5 Hz, 1H), 3.68 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.9, 164.3, 136.3, 135.7, 134.0, 133.9, 130.8, 129.2, 128.7, 128.5, 127.55, 126.88, 125.2, 123.1, 78.4, 52.6, 48.9; trans-38: 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 7.9 Hz, 1H), 7.63 (app. t, 1H), 7.51 (app. t, 1H), 7.40 (d, J = 7.4 Hz, 2H), 7.42−

7.29 (m, 4H), 6.79 (d, J = 15.9 Hz, 1H), 6.20 (dd, J = 6.8, 15.9 Hz, 1H), 5.60−5.54 (m, 1H), 4.11 (d, J = 6.3 Hz, 1H), 3.80 (s, 3H). 13 C{1H} NMR (100 MHz, CDCl3): δ 170.1, 163.7, 135.5, 135.4, 135.2, 134.3, 130.5 128.9, 128.69, 128.6, 127.51, 126.85, 124.7, 123.9, 79.4, 52.9, 49.1; IR (neat): 2954, 1732, 1713, 1606, 1439, 1311, 1266, 1230, 1164, 1154, 1117, 710, 690, 607; HRMS (APCI) m/z: [M + Na]+ Calcd for C19H16O4Na 331.0940; Found 331.0943. Asterisk (*) refers to a mixture of cis-38:trans-38 in a 66:34 ratio. Methyl-3-(but-3-en-1-yl)-1-oxoisochromane-4-carboxylate (cis39, trans-39). Prepared according to general procedure B, using freshly distilled 4-pentenal (26.0 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 18 h to give a diastereomeric mixture of carboxylic acids in a 74:26 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 85:15 hexanes:EtOAc, cis-39 and trans39 were isolated combined as a pale yellow oil (61.4 mg, 96%). CSPHPLC analysis: Chiralcel IA (4.6 mm × 25 cm), n-hexane/IPA: 90/ 10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: cis39 8.4 min (minor enantiomer) and 13.4 min (major enantiomer).); trans-39 9.2 min (major enantiomer) and 10.7 min (minor enantiomer). TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.47; [α]20D = −5.9 (c = 0.07, CHCl3); * cis-39: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.3 Hz, 1H), 7.59 (app. t, 1H), 7.50 (app. t, 1H), 7.32 (d, J = 8.3 Hz, 1H), 5.90−5.76 (m, 1H), 5.12 (dd, J = 1.5, 17.1 Hz, 1H), 5.04 (dd, J = 1.5, 10.1 Hz, 1H), 4.68 (ddd, J = 3.3, 4.8, 8.7 Hz, 1H), 3.87 (d, J = 3.3 Hz, 1H), 3.69 (s, 3H), 2.49−2.25 (m, 2H), 2.13−1.97 (m, 1H), 1.95−1.81 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 164.7, 136.7, 133.7, 130.7, 129.0, 127.3, 125.4, 116.1, 77.7, 52.6, 47.8, 31.8, 29.2; trans-39: 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 7.6 Hz, 1H), 7.61 (app. t, 1H), 7.49 (app. t, 1H), 7.24 (d, J = 7.9 Hz, 1H), 5.85−5.74 (m, 1H), 5.09 (dd, J = 1.6, 17.3 Hz, 1H), 5.03 (dd, J = 1.6 Hz, 1H), 4.95 (ddd, J = 4.0, 6.6 Hz, 1H), 3.94 (d, J = 6.6 Hz, 1H), 3.81 (s, 3H), 2.43−2.20 (m, 2H), 1.96−1.82 (m, 1H), 1.77−1.64 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.6, 163.8, 136.6, 135.8, 134.1, 130.5, 128.7, 126.6, 124.6, 116.0, 78.3, 52.8, 48.4, 32.9, 29.1; IR (neat): 2951, 1720, 1640, 1604, 1458, 1435, 1240, 1159, 1116, 1086, 1030, 996, 916, 768, 709. HRMS (APCI) m/ z: [M + H]+ Calcd for C15H17O4 261.1121; Found 261.1116. Asterisk (*) refers to a mixture of cis-39: trans-39 in a 74:26 ratio. Methyl-3-((E)-6-ethoxy-6-oxohex-4-en-1-yl)-1-oxoisochromane4-carboxylate (cis-40, trans-40). Prepared according to general procedure B, using aldehyde S1 (42.0 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 18 h to give a diastereomeric mixture of carboxylic acids in a 73:27 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 85:15 hexanes:EtOAc, cis-40 and trans-40 were isolated combined as a pale yellow oil (71.6 mg, 84%).CSP-HPLC analysis: Chiralcel IA (4.6 mm × 25 cm), hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 221 nm, retention times: cis- 40 42.9 min; trans- 40 20.9 min (minor enantiomer) and 23.5 min (major enantiomer).TLC (hexanes/ EtOAc, 8:2 v/v): Rf = 0.16; [α]20D = −3.4 (c = 0.01, CHCl3); * cis- 40: 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 7.1 Hz, 1H), 7.56 (app. t, 1H), 7.49 (app. t, 1H), 7.29 (d, J = 7.8 Hz, 1H), 6.96−6.88 (m, 1H), 5.84 (d, J = 15.5 Hz, 1H), 4.67−4.55 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.84 (d, J = 2.8 Hz, 1H), 3.66 (s, 3H), 2.29−2.25 (m, 2H), 1.92−1.89 (m, 2H), 1.76−1.64 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.1, 165.5, 164.5, 147.8, 136.6, 133.8, 130.8, 129.1, 127.5, 125.4, 122.1, 78.3, 60.2, 52.6, 47.9, 32.2, 31.6, 23.8, 14.3; trans- 40: 1H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 7.8 Hz, 1H), 7.54 (app. t, 1H), 7.48 (app. t, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.96−6.88 (m, 1H), 5.78 (d, J = 14.5 Hz, 1H), 4.97− 4.84 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.89 (d, J = 6.9 Hz, 1H), 3.79 (s, 3H), 2.24−2.22 (m, 2H) 1.87−1.82 (m, 2H), 1.76−1.64 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 166.5, 163.7, 147.7, 135.8, 134.2, 130.6, 128.8, 127.2, 124.5, 122.1, 78.6, 60.2, 52.8, 48.5, 33.0, 31.4, 23.4, 14.2; IR (neat): 2953, 1717, 1652, 1459, 1367, 1265, 1159, 1032, 976, 706, 625; HRMS (ESI) m/ z: [M + Na]+ Calcd for C19H22O6Na 369.1308; Found 369.1309. Asterisk (*) refers to a mixture of cis-40: trans-40 in a 73:27 ratio. 15505


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a 60:40 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 85:15 hexanes:EtOAc, the diastereomer cis-43 was isolated as a white solid (47.9 mg, 54%, 92% ee). CSP-HPLC analysis: Chiralcel IA (4.6 mm × 25 cm), n-hexane/ IPA: 95/5, 0.5 mL min−1, RT, UV detection at 221 nm, retention times: 87.1 min (minor enantiomer) and 91.2 min (major enantiomer). Mp 135−137 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.35; [α]20D = −7.6 (c = 0.03, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 7.8 Hz, 1H), 7.65 (app. t, 1H), 7.60−7.54 (m, 3H), 7.39 (m, 3H), 5.75 (d, J = 3.6 Hz, 1H), 4.14 (d, J = 3.6 Hz, 1H), 3.49 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.4, 164.1, 136.0, 135.2, 134.1, 131.8, 131.0, 129.4, 127.4, 127.3, 125.1, 122.8, 78.7, 52.5, 50.3; IR (neat): 3061, 3018, 2952, 1725, 1601, 1490, 1258, 1009, 822, 736, 692; HRMS (ESI) m/z: [M − H]− Calcd for C17H12O4Br 358.9924; Found 358.9920. Methyl-3-(4-bromophenyl)-1-oxoisochromane-4-carboxylate (trans-43).6 Prepared according to general procedure B, using recrystallized p-bromobenzaldehyde (45.5 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 22 h to give a diastereomeric mixture of carboxylic acids in a 60:40 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 85:15 hexanes:EtOAc, the diastereomer trans-43 was isolated as a white solid (31.7 mg, 36%, 74% ee). CSP-HPLC analysis. Chiralcel IA (4.6 mm × 25 cm), hexane/IPA: 95/5, 0.5 mL min−1, RT, UV detection at 254 nm, retention times: 70.0 min (minor enantiomer) and 80.7 min (major enantiomer). Mp 137−138 °C (lit.,6 mp 138−140 °C); TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.38; 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.9 Hz, 1H), 7.61 (app. t, 1H), 7.55−7.45 (m, 3H), 7.28 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 5.80 (d, J = 8.5 Hz, 1H), 4.28 (d, J = 8.5 Hz, 1H), 3.71 (s, 3H). Methyl 3-(4-Chlorophenyl)-1-oxoisochroman-4-carboxylate (cis44). Prepared according to general procedure B, using recrystallized 4chlorobenzaldehyde (34.6 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 36 h to give a diastereomeric mixture of carboxylic acids in a 59:41 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 80:20 hexanes:EtOAc, the diastereomer cis-44 was isolated as white solid (42.1 mg, 54%, 85% ee) CSP-HPLC analysis: Chiralcel IA (4.6 mm × 25 cm), n-hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 221 nm, retention times: 21.3 min (minor enantiomer) and 22.8 min (major enantiomer). Mp 65−68 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.70; [α]20D = −11.6 (c = 0.03, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 7.8 Hz, 1H), 7.60 (app. t, 1H), 7.56 (app. t, 1H), 7.45−7.36 (m, 5H), 5.74 (d, J = 3.4 Hz, 1H), 4.12 (d, J = 3.4 Hz, 1H), 3.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.4, 164.1, 136.0, 134.7, 134.6, 134.2, 131.0, 129.4, 128.9, 127.4, 127.0, 125.1, 78.6, 52.5, 50.4; IR (neat): 2953, 2926, 2862, 1736, 1709, 1602, 1459, 1261, 1001, 826, 740; HRMS (ESI) m/z: [M+ H]+ Calcd for C17H14O4Cl 317.0580; Found: 317.0568. Methyl 3-(4-Chlorophenyl)-1-oxoisochroman-4-carboxylate (trans-44).6 Prepared according to general procedure B, using recrystallized 4-chlorobenzaldehyde (34.6 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 36 h to give a diastereomeric mixture of carboxylic acids in a 59:41 ratio (cis:trans). After esterification and purification by flash column chromatography eluting with 80:20 hexanes:EtOAc, the diastereomer trans-44 was isolated as a white solid (29.6 mg, 38%, 78% ee). CSP-HPLC analysis Chiralcel IA (4.6 mm × 25 cm), hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: 20.2 min (minor enantiomer) and 23.0 min (major enantiomer). Mp 71−73 °C (lit.,6 mp 70−72 °C); TLC (hexanes/ EtOAc, 8:2 v/v): Rf = 0.6; 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.7 Hz, 1H), 7.61 (app. t, 1H), 7.50 (app. t, 1H), 7.39−7.29 (m, 4H), 7.19 (d, J = 7.7 Hz, 1H), 5.82 (d, J = 8.7 Hz, 1H), 4.30 (d, J = 8.7 Hz, 1H), 3.71 (s, 3H). Methyl 3-(3-Bromophenyl)-1-oxoisochromane-4-carboxylate (cis-45). Prepared according to general procedure B, using freshly distilled 3-bromobenzaldehyde (28.7 μL, 0.246 mmol) and

Methyl-3-(2-((tert-butoxycarbonyl)amino)ethyl)-1-oxoisochromane-4-carboxylate (cis-41, trans-41). Prepared according to general procedure B, using aldehyde S2 (42.6 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 24 h to give a diastereomeric mixture of carboxylic acids in a 70:30 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 70:30 hexanes:EtOAc, cis-41 and trans-41 were isolated combined as a pale yellow oil (64.4 mg, 75%). CSP-HPLC analysis: Chiralcel ODH (4.6 mm × 25 cm), hexane/IPA: 98/2, 0.5 mL min−1, RT, UV detection at 254 nm, retention times: cis-41 364.7 min; trans-41 220.1 min (minor enantiomer) and 190.1 min (major enantiomer).TLC (hexanes/ EtOAc, 8:2 v/v): Rf = 0.17; [α]20D = −4.4 (c = 0.02, CHCl3); * cis41: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 7.8 Hz, 1H), 7.61 (app. t, 1H), 7.51 (app. t, 1H), 7.34 (d, J = 7.4 Hz, 1H), 4.88−4.77 (bs, 1H), 4.76−4.68 (m, 1H), 3.95 (d, J = 3.5 Hz, 1H), 3.69 (s, 3H), 3.48−3.33 (m, 2H), 2.12−2.03 (m, 2H), 1.44 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.2, 164.5, 156.1, 136.7, 133.8, 130.7, 129.1, 127.4, 125.2, 77.2, 67.9, 52.6, 47.7, 36.9, 33.1, 28.3; trans-41: 1 H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 6.2 Hz, 1H), 7.63 (app. t, 1H), 7.49 (app. t, 1H), 7.27 (d, J 8.0 Hz, 1H), 5.04−4.96 (m, 1H), 4.88−4.77 (bs, 1H), 3.96 (d, J = 5.6 Hz, 1H), 3.82 (s, 3H), 3.48−3.33 (m, 2H), 1.92−1.89 (m, 1H), 1.84−1.77 (m, 1H), 1.45 (s, 9H); 13 C{1H} NMR (100 MHz, CDCl3): δ 170.3, 163.5, 155.9, 135.7, 134.3, 130.5, 128.8, 127.4, 124.4, 79.5, 77.2, 52.8, 48.2, 36.7, 30.1, 28.3; IR (neat): 3383, 2976, 1705, 1609, 1516, 1458, 1366, 1241, 1161, 1086, 1031, 994, 734, 605; HRMS (ESI) m/z: [M − H]− Calcd for C18H22NO6 348.1447; Found 348.1450. Asterisk (*) refers to a mixture of cis-41: trans-41 in a 84:16 ratio. Methyl 1-Oxo-3-phenylisochroman-4-carboxylate (cis-42). Prepared according to general procedure B, using freshly distilled benzaldehyde (25.0 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was allowed to stir for 5 days to give a diastereomeric mixture of carboxylic acids in a 61:39 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 80:20 hexanes:EtOAc, the diastereomer cis-42 was isolated as a white solid (37.5 mg, 54%, 92% ee). CSPHPLC analysis: Chiralcel IA (4.6 mm × 25 cm), n-hexane/IPA: 90/ 10, 1.0 mL min−1, RT, UV detection at 221 nm, retention times:17.6 min (minor enantiomer) and 22.3 min (major enantiomer). Mp 115− 117 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.41; [α]20D = −4.3 (c = 0.02, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 7.8 Hz, 1H), 7.63 (app. t, 1H), 7.56 (app. t, 1H), 7.52−7.48 (m, 2H), 7.44 (app. t, 2H), 7.42−7.36 (m, 2H), 5.78 (d, J = 3.7 Hz, 1H), 4.14 (d, J = 3.7 Hz, 1H), 3.50 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.6, 164.4, 136.3, 136.2, 134.0, 131.0, 129.3, 128.7, 128.6, 127.3, 125.6, 125.3, 79.4, 52.3, 50.7; IR (neat): 2955, 1721, 1601, 1454, 1431, 1244, 1080, 997, 782, 701; HRMS (APCI) m/z: [M − H]− Calcd for C17H13O4 281.0819; Found 281.0811. Methyl 1-Oxo-3-phenylisochroman-4-carboxylate (trans-42).6 Prepared according to general procedure B, using freshly distilled benzaldehyde (25 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was allowed to stir for 5 days to give a diastereomeric mixture of carboxylic acids in a 61:39 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 80:20 hexanes:EtOAc, the diastereomer trans-42 was isolated as a white solid (24.3 mg, 35%, 64% ee). CSPHPLC analysis. Chiralcel IA (4.6 mm × 25 cm), hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: trans-42 17.0 min (minor enantiomer) and 19.5 min (major enantiomer). Mp 118−120 °C (lit.,6 mp 129−132 °C); TLC (hexanes/EtOAc, 8:2 v/ v): Rf = 0.38. (lit.,6 mp 129−132 °C); 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.0 Hz, 1H), 7.60 (app. t, 1H), 7.49 (app. t, 1H), 7.44− 7.30 (m, 5H), 7.20 (d, J = 8.0 Hz, 1H), 5.86 (d, J = 8.3 Hz, 1H), 4.34 (d, J = 8.3 Hz, 1H), 3.69 (s, 3H). Methyl-3-(4-bromophenyl)-1-oxoisochromane-4-carboxylate (cis-43). Prepared according to general procedure B, using recrystallized p-bromobenzaldehyde (45.5 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 22 h to give a diastereomeric mixture of carboxylic acids in 15506


Note


hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: 32.2 min (minor enantiomer) and 37.9 min (major enantiomer). Mp 156−158 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.32; [α]20D = +6.3 (c = 0.04 CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.64 (app. t, 1H), 7.57−7.45 (m, 3H), 7.22 (d, J = 7.9 Hz, 1H), 5.95 (d, J = 8.2 Hz, 1H), 4.35 (d, J = 8.2 Hz, 1H), 3.94 (s, 3H), 3.73 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 169.8, 166.5, 163.7, 141.4, 135.7, 134.7, 130.8, 130.7, 130.0, 129.0, 126.8, 126.7, 124.4, 80.0, 52.8, 52.3, 50.6; IR (neat): 3010, 2158, 2029, 1735, 1020, 1609, 1425, 1280, 1250, 1184, 1279, 1107, 1056, 1018, 921, 869, 736, 641; HRMS (APCI): m/z: [M + Na]+ Calcd for C19H16O6Na 363.0839; Found: 363.0835 Methyl 3-(4-Cyanophenyl)-1-oxoisochromane-4-carboxylate (cis-47). Prepared according to general procedure B, using recrystallized 4-cyanobenzaldehyde (32.3 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 48h to give a diastereomeric mixture of carboxylic acids in a 58:42 ratio (cis:trans). After esterification and purification by flash column chromatography eluting with 75:25 hexanes:EtOAc, the diastereomer cis-47 was isolated as a white solid (78.4 mg, 51%, 89% ee). CSPHPLC analysis: ACQUITY UPC2, Trefoil AMY1, 2.5 μm (3.0 × 150 mm). ABPR: 1500 (psi). A (CO2) = 97%/B (Ethanol/IPA 1:1, v:v) = 3%, 1.2 mL min−1, 30 °C, UV detection at 254 nm, retention times: 3.5 min (major enantiomer) and 3.6 min (minor enantiomer). Mp 126−128 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.25; [α]20D = −1.7 (c = 0.14, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.68−7.61 (m, 3H), 7.56 (app. t, 1H), 7.39 (d, J = 7.6, 1H), 5.82 (d, J = 3.6 Hz, 1H), 4.16 (d, J = 3.6 Hz, 1H), 3.45 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.1, 163.6, 141.3, 135.7, 134.3, 132.5, 131.1, 129.6, 127.5, 126.5, 124.9, 118.3, 112.7, 78.2, 52.5, 49.9; IR (neat): 2922, 2231, 1742, 1609, 1458, 1356, 1275, 1164, 1080, 1064, 971, 816, 704, 557; HRMS (ESI) m/z: [M − H]− Calcd for C18H12NO4306.0771; Found: 306.0784. Methyl 3-(4-Cyanophenyl)-1-oxoisochromane-4-carboxylate (trans-47). Prepared according to general procedure B, using recrystallized 4-cyanobenzaldehyde (32.3 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 48h to give a diastereomeric mixture of carboxylic acids in a 58:42 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 75:25 hexanes:EtOAc, the diastereomer trans-47 was isolated as yellow oil (67.6 mg, 42%, 60% ee). CSP-HPLC analysis. ACQUITY UPC2, Trefoil CEL2, 2.5 μm (3.0 × 150 mm). ABPR: 1500 (psi). A (CO2) = 97%/B (Ethanol/ ACN 1:1, v:v) = 3%, 1.2 mL min−1, 30 °C, UV detection at 254 nm, retention times: 3.1 min (minor enantiomer) and 3.4 min (major enantiomer). TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.23, [α]20D = +19.1 (c = 0.05, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.65 (app. t, 1H), 7.58−7.51 (m, 3H), 7.22 (d, J = 7.7 Hz, 1H), 5.94 (d, J = 8.5 Hz, 1H), 4.32 (d, J = 8.5 Hz, 1H), 3.76 (s, 3H);13C{1H} NMR (100 MHz, CDCl3): δ 169.6, 163.4, 141.7, 135.4, 134.7, 132.6, 130.8, 129.2, 127.6, 126.7, 124.2, 118.2, 113.2, 78.6, 52.9, 50.5; IR (neat): 2921, 2215, 1730, 1609, 1454, 1356, 1272, 1167, 1078, 1061, 956, 811, 701, 557; HRMS (ESI): m/z: [M − H]− Calcd for C18H12NO4306.0771; Found: 306.0767. Methyl 3-(4-Methoxyphenyl)-1-oxoisochroman-4-carboxylate (cis-48). Prepared according to general procedure B, using freshly distilled 4-methoxybenzaldehyde (30 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was allowed to stir for 48 h to give a diastereomeric mixture of carboxylic acids in a 58:42 ratio (cis:trans). After esterification and purification by flash column chromatography eluting with 85:15 hexanes:EtOAc, the diastereomer cis-48 was isolated as a white solid (26.9 mg, 35%, 94% ee). CSP-HPLC analysis: Chiralpak IA (4.6 mm × 25 cm), n-hexane/IPA: 97/3, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: 110.8 min (minor enantiomer) and 124.4 min (major enantiomer). Mp 75−77 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.52; [α]20D = −7.1 (c = 0.04, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 7.8 Hz, 1H), 7.61 (app. t, 1H), 7.53

homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 40 h to give a diastereomeric mixture of carboxylic acids in a 55:45 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 85:15 hexanes:EtOAc, the diastereomer cis-45 was isolated as a white solid (39.1 mg, 44%, 88% ee). CSP-HPLC analysis: Chiralcel IA (4.6 mm × 25 cm), n-hexane/ IPA: 95/5, 1.0 mL min−1, RT, UV detection at 221 nm, retention times: 58.7 min (minor enantiomer) and 78.6 min (major enantiomer). Mp 92−94 °C; TLC (hexanes/EtOAc, 8/2 v/v): Rf = 0.50; [α]20D = −5.9 (c = 0.03, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 7.9 Hz, 1H), 7.67−7.59 (m, 2H), 7.56−7.49 (m, 2H), 7.42−7.32 (m, 2H) 7.30−7.26 (m, 1H), 5.73 (d, J = 3.7 Hz, 1H), 4.12 (d, J = 3.7 Hz, 1H), 3.47 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.4, 164.0, 138.4, 135.9, 134.2, 131.9, 131.1, 130.2, 129.4, 128.8, 127.4, 125.1, 124.3, 122.8, 78.4, 52.5, 50.4; IR (neat): 2947, 1722, 1601, 1458, 1358, 1286, 1261, 1225, 1112, 1085, 1056, 996, 971, 989, 787, 717, 689, 638, 584; HRMS (APCI) m/z: [M + Na]+ Calcd for C17H13BrO4Na 382.9888; Found: 382.9889. Methyl 3-(3-Bromophenyl)-1-oxoisochromane-4-carboxylate (trans-45). Prepared according to general procedure B, using freshly distilled 3- bromobenzaldehyde (28.7 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 40 h to give a diastereomeric mixture of carboxylic acids in a 55:45 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 85:15 hexanes:EtOAc, the diastereomer trans-45 was isolated as a white solid (35.3 mg, 39%, 72% ee). CSP-HPLC analysis. Chiralcel IA (4.6 mm × 25 cm), hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: 16.7 min (minor enantiomer) and 18.8 min (major enantiomer). Mp 100−105 °C; TLC (hexanes/EtOAc, 8/2 v/v): Rf = 0.46; [α]20D = +8.8 (c = 0.05, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 7.9 Hz, 1H), 7.64 (app. t, 1H), 7.59 (s, 1H), 7.55−7.52 (m, 1H), 7.51−7.49 (m, 1H), 7.36−7.31 (m, 1H), 7.28−7.20 (m, 2H), 5.83 (d, J = 8.7 Hz, 1H), 4.32 (d, J = 8.7 Hz, 1H), 3.74 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 169.8, 163.7, 138.8, 135.8, 134.6, 132.3, 130.7, 130.3, 129.9, 129.0, 126.7, 125.4, 124.3, 122.8, 79.7, 52.8, 50.7; IR (neat)/cm−1: 2940, 1720, 1601, 1455, 1348, 1285, 1260, 1235, 1112, 1075, 1054, 995, 971, 989, 783, 713, 687, 584; HRMS (APCI) m/z: [M + H]+ Calcd for C17H14BrO4 360.9888; Found: 360.9887. Methyl 3-(4-(Methoxycarbonyl)phenyl)-1-oxoisochromane-4carboxylate (cis-46). Prepared according to general procedure B, using recrystallized methyl 4-formylbenzoate (40.4 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 48 h to give adiastereomeric mixture of carboxylic acids in a 59:41 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 70:30 hexanes:EtOAc, the diastereomer cis-46 was isolated as a white solid (46.0 mg, 55%, 94% ee). CSP-HPLC analysis: Chiralcel IA (4.6 mm × 25 cm), hexane/ IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: 33.8 min (major enantiomer) 55.7 min (minor enantiomer). Mp 144−146 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.31; [α]20D = −10.4 (c = 0.04, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.3 Hz, 2H), 7.67 (app. t, 1H), 7.66- 7.53 (m, 3H), 7.38 (d, J = 7.0 Hz, 1H), 5.82 (d, J = 3.5 Hz, 1H), 4.17 (d, J = 3.5 Hz, 1H), 3.93 (s, 3H), 3.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.3, 166.6, 164.1, 141.2, 136.0, 134.4, 131.1, 130.5, 129.9, 129.5, 127.4, 125.7, 125.1, 78.8, 52.5, 52.3, 50.3; IR (neat): 3016, 2162, 2030, 1748, 1611, 1428, 1280, 1250, 1193, 1072, 921, 870, 742, 642; HRMS (APCI) m/z: [M + Na]+ Calcd for C19H16O6Na 363.0839; Found: 363.0839. Methyl 3-(4-(Methoxycarbonyl)phenyl)-1-oxoisochromane-4carboxylate (trans-46). Prepared according to general procedure B, using recrystallized methyl 4-formylbenzoate (40.4 mg, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 48 h to give a diastereomeric mixture of carboxylic acids in a 59:41 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 70:30 hexanes:EtOAc, the diastereomer trans-46 was isolated as a white solid (31.8 mg, 38%, 83% ee). CSP-HPLC analysis. Chiralcel IA (4.6 mm × 25 cm), 15507


Note


ee). CSP-HPLC analysis: Chiralpak IA (4.6 mm × 25 cm), hexane/ IPA: 97/3, 1.0 mL min−1, RT, UV detection at 221 nm, retention times: 21.8 min (minor enantiomer) and 25.8 min (major enantiomer). Mp 110−112 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.35; [α]20D = −3.2 (c = 0.01, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 7.9 Hz, 1H), 7.62 (app. t, 1H), 7.54 (app. t, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.35 (dd, J = 1.2, 5.1 Hz, 1H), 7.16 (d, J = 1.2, 3.7 Hz, 1H), 7.03 (dd, J = 3.7, 5.1 Hz, 1H), 6.00 (d, J = 3.6 Hz, 1H), 4.20 (d, J = 3.6 Hz, 1H), 3.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.6, 163.9, 138.4, 135.9, 134.1, 131.1, 129.4, 127.4, 126.8, 126.1, 125.6, 125.0, 52.7, 50.7, 30.9; IR (neat): 3104, 3011, 2951, 2925, 1727, 1703, 1605, 1459, 1431, 1359, 1332, 1226, 1081, 943, 714; HRMS (APCI) m/z: [M + H] + Calcd for C15H13O4S 289.0529; Found: 289.0518. Methyl 1-Oxo-3-(thiophen-2-yl)isochroman-4-carboxylate (trans-50).6 Prepared according to general procedure B, freshly distilled 2-thiophenecarboxaldehyde (23 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol).The reaction was allowed to stir for 5 days to give a diastereomeric mixture of carboxylic acids in a 56:44 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 75:25 hexanes:EtOAc, the diastereomer trans-50 was isolated as a white solid (26.2 mg, 37%, 57% ee). CSP-HPLC analysis. Chiralpak IA (4.6 mm × 25 cm), hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: 30.3 min (minor enantiomer) and 32.9 min (major enantiomer). Mp 110−112 °C (lit.,6 126−128 °C); TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.36; 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 7.9 Hz, 1H), 7.63 (app. t, 1H), 7.51 (app. t, 1H), 7.33− 7.21 (m, 2H), 7.09−7.01 (m, 1H), 6.96−6.89 (m, 1H), 6.19 (d, J = 6.1 Hz, 1H), 4.35 (d, J = 6.1 Hz, 1H), 3.75 (s, 3H). Methyl 1-Oxo-3-(pyridin-2-yl)isochromane-4-carboxylate (cis51). Prepared according to general procedure B, using freshly distilled pyridin-2 carboxaldehyde (23.5 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 4 days to give a diastereomeric mixture of carboxylic acids in a 61:39 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 70:30 hexanes:EtOAc, the diastereomer cis-51 was isolated as a thick yellow oil (40.4 mg, 58%, 80% ee). CSPHPLC analysis: Chiralcel OJ-H (4.6 mm × 25 cm), hexane/IPA: 90/ 10, 1.0 mL min−1, RT, UV detection at 221 nm, retention times: 52.0 min (major enantiomer) and 78.3 min (minor enantiomer). TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.20; [α]20D = −1.14 (c = 0.03, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 4.8 Hz, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.86−7.78 (m, 2H), 7.65 (app. t, 1H), 7.55 (app. t, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.30 (m, 1H), 5.84 (d, J = 3.6 Hz, 1H), 4.63 (d, J = 3.6 Hz, 1H), 3.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.8, 164.0, 156.0, 149.0, 137.0, 136.4, 134.2, 130.9, 129.2, 127.9, 125.1, 123.2, 120.7, 79.6, 52.3, 47.9; IR (neat): 2968, 1715, 1601, 1453, 1420, 1287,1253, 1119, 1002, 862, 824, 731, 720; HRMS (ESI) m/z: [M − H]− Calcd for C16H12NO4 282.0766; Found 282.0769. Methyl 1-Oxo-3-(pyridin-2-yl)isochromane-4-carboxylate (trans51). Prepared according to general procedure B, freshly distilled pyridin-2 carboxaldehyde (385, 23.5 μL, 0.246 mmol) and homophthalic anhydride (147, 39.9 mg, 0.246 mmol). The reaction was stirred for 4 days to give a diastereomeric mixture of carboxylic acids in a 61:39 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 70:30 hexanes:EtOAc, the diastereomer trans-51 was isolated as a thick yellow oil (22.3 mg, 32%, 25% ee). CSP-HPLC analysis. Chiralcel IA (4.6 mm × 25 cm), hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: 26.3 min (major enantiomer) and 32.8 min (minor enantiomer). TLC (hexanes/EtOAc, 8/2 v/v): Rf = 0.30; [α]20D = +0.3 (c = 0.04, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 4.4 Hz, 1H), 8.13 (d, 1H, J = 7.8 Hz, 1H), 7.69 (app. t, 1H), 7.57 (app. t, 1H), 7.53 (d, 1H, J = 7.9 Hz, 1H), 7.43 (app. t, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.23−7.17 (m, 1H), 6.13 (d, J = 4.5 Hz, 1H), 4.89 (d, J = 4.5 Hz, 1H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 170.6, 163.6, 156.3, 149.0, 137.1, 135.2, 134.2, 130.2, 128.6, 128.3, 124.6, 123.2, 121.3, 79.9, 52.8, 47.0; IR (neat): 2969, 1715, 1601,

(app. t, 1H), 7.40−7.34 (m, 3H), 6.93 (d, J = 8.6 Hz, 2H), 5.72 (d, J = 3.6, 1H), 4.01 (d, J = 3.6 Hz, 1H), 3.83 (s, 3H), 3.48 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 168.8, 164.6, 159.7, 136.4, 133.9, 130.9, 129.2, 128.2, 127.3, 126.9, 125.3, 113.9, 79.2, 55.3, 52.4, 50.8; IR (neat): 3012, 2959, 2930, 2834, 1710, 1604, 1518, 1248, 990, 734; HRMS (ESI) m/z: [M + Na] + Calcd for C18H16O5Na 335.0895; Found 335.0888. Methyl 3-(4-Methoxyphenyl)-1-oxoisochroman-4-carboxylate (trans-48).6 Prepared according to general procedure B, using freshly distilled 4-methoxybenzaldehyde (30.0 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was allowed to stir for 48 h to give a diastereomeric mixture of carboxylic acids in a 58:42 (cis:trans) ratio. After esterification and purification by flash column chromatography eluting with 85:15 hexanes:EtOAc, the diastereomer trans-48 was isolated and purified as a white solid (23.1 mg, 30%, 40% ee). CSP-HPLC analysis. Chiralpak IA (4.6 mm × 25 cm), hexane/IPA: 97/3, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: 26.5 min (minor enantiomer) and 29.3 min (major enantiomer). Mp 80−82 °C, (lit.,6 mp 82−84 °C); TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.57; 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 7.8 Hz, 1H), 7.60 (app. t, 1H), 7.49 (app. t, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 5.77 (d, J = 9.0 Hz, 1H), 4.34 (d, J = 9.0 Hz, 1H), 3.80 (s, 3H), 3.69 (s, 3H). Methyl 1-Oxo-3-(o-tolyl) Isochromane-4-carboxylate (cis-49). Prepared according to general procedure B, using freshly distilled 2methylbenzaldehyde (28.4 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 4 days to give a diastereomeric mixture of carboxylic acids in a 67:33 ratio (cis:trans). After esterification and purification by flash column chromatography eluting with 85:15 hexanes: EtOAc, the diastereomer cis-49 was isolated as a white solid (42.3 mg, 58%, 95% ee). CSPHPLC analysis: ACQUITY UPC2, Trefoil AMY1, 2.5 μm (3.0 × 150 mm). ABPR: 1500 (psi). A (CO2) = 99%/B (Ethanol/ACN/IPA 1:1:1, v:v:v) = 1%, 1.2 mL min−1, 30 °C, UV detection at 212 nm, retention times: 3.2 min (minor enantiomer) and 3.4 min (major enantiomer). Mp 108−110 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.38; [α]20D = −15.0 (c = 0.04, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 7.7 Hz, 1H), 7.64−7.60 (m, 2H), 7.55 (app. t, 1H), 7.35 (d, J = 7.3 Hz, 1H) 7.28−7.26 (m, 2H), 7.23−7.20 (m, 1H), 5.93 (d, J = 3.5 Hz, 1H), 4.01 (d, J = 3.5 Hz, 1H), 3.44 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.7, 164.7, 136.4, 134.2, 133.9, 133.5, 131.0, 130.6, 129.3, 128.6, 127.3, 126.4, 125.9, 125.4, 76.9, 52.3, 48.6, 19.1; IR (neat): 3071, 3024, 2952, 2929, 2844, 1718, 1602, 1457, 1250, 1003, 915, 736; HRMS (ESI) m/z: [M+ + Na] Calcd for C18H16O4Na 319.0940; Found 319.0932. Methyl 1-Oxo-3-(o-tolyl) Isochromane-4-carboxylate (trans49).6 Prepared according to general procedure B, using freshly distilled 2-methylbenzaldehyde (28.4 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was stirred for 4 days to give a diastereomeric mixture of carboxylic acids in a 67:33 ratio (cis:trans). After esterification and purification by flash column chromatography eluting with 85:15 hexanes:EtOAc, the diastereomer trans-49 was isolated as a white solid (20.4 mg, 28%, 82% ee). CSP-HPLC analysis. Chiralcel ODH (4.6 mm × 25 cm), hexane/IPA: 83/17, 0.5 mL min−1, RT, UV detection at 254 nm, retention times: 22.3 min (minor enantiomer) and 35.6 min (major enantiomer). Mp 109−110 °C; (lit.,6 114−116 °C); TLC (hexanes/ EtOAc, 8:2 v/v): Rf = 0.41; 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 7.7 Hz, 1H), 7.62 (app. t, 1H), 7.51 (app. t, 1H), 7.31 (d, J = 7.7 Hz, 1H) 7.28−7.13 (m, 4H), 6.08 (d, J = 8.7 Hz, 1H), 4.48 (d, J = 8.7 Hz, 1H), 3.68 (s, 3H), 2.45 (s, 3H). Methyl 1-Oxo-3-(thiophen-2-yl)isochroman-4-carboxylate (cis50). Prepared according to general procedure B, using freshly distilled 2-thiophenecarboxaldehyde (23 μL, 0.246 mmol) and homophthalic anhydride (1, 39.9 mg, 0.246 mmol). The reaction was allowed to stir for 6 days to give a diastereomeric mixture of carboxylic acids in a 56:44 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 75:25 hexanes:EtOAc, the diastereomer cis-50 was isolated as a brown solid (35.5 mg, 50%, 86% 15508


Note


diastereomer cis-60. Upon esterification, the reaction gave a diastereomeric mixture of esters in a 90:10 ratio (cis:trans). The major diastereomer cis-60 was then isolated by flash column chromatography, eluting with 95:5 hexanes:EtOAc, as a white solid (83.3 mg, 85%, 99% ee). CSP-HPLC analysis: ACQUITY UPC2, Trefoil AMY1, 2.5 μm (3.0 × 150 mm). ABPR: 1500 (psi). A (CO2) = 97%/B (Ethanol/CAN/IPA 1:1:1, v:v) = 3%, 1.2 mL min−1, 30 °C, UV detection at 254 nm, retention times: 2.9 min. Mp 142−144 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.67; [α]20D = −2.8 (c = 0.04, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.49−7.45 (m, 2H), 7.44− 7.39 (m, 5H), 7.38−7.35 (m, 4H), 7.35−7.29 (m, 3H), 7.21- 7.19 (m, 1H), 6.52 (s, 1H), 5.34 (dd, J = 1.4, 10.6 Hz, 1H), 4.39 (d, J = 10.6 Hz, 1H), 3.79 (d, J = 1.4 Hz, 1H), 3.64 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.1, 164.4, 152.3, 140.2, 139.9, 134.6, 130.9, 129.2, 129.1, 128.6, 128.3, 128.2, 127.5, 126.9, 126.3, 116.7, 79.7, 53.7, 52.8, 44.9; IR (neat): 3088, 2971, 2923, 1660, 1592, 1506, 1472, 1311, 1217, 1072, 998, 768, 642; HRMS (ESI) m/z: [M + Na]+ Calcd for C26H22O4Na 421.1410; Found: 421.1407.21

1455, 1425, 1289,1253, 1119, 1004, 862, 824, 733, 723; HRMS (ESI): m/z: [M − H]− Calcd for C16H12NO4 282.0766; Found 282.0760. Methyl 7-Bromo-1-oxo-3-(pentan-3-yl)isochromane-4-carboxylate (cis-54). Prepared according to general procedure B, using freshly distilled 2-ethylbutaraldehyde (53, 30.4 μL, 0.246 mmol) and anhydride 52 (59.3 mg, 0.246 mmol). The reaction was stirred for 9 days to give a diastereomeric mixture of carboxylic acids in a 84:16 ratio (cis:trans). After esterification, the diastereomer cis-54 was isolated and purified by flash column chromatography, eluting with 90:10 hexanes:EtOAc to give cis-54 as a white solid (62.0 mg, 71%, 99% ee). CSP-HPLC analysis: Chiralcel IA (4.6 mm × 25 cm), hexane/IPA: 90/10, 1.0 mL min−1, RT, UV detection at 254 nm, retention times: 14.5 min (major enantiomer). Mp 72−75 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.67; [α]20D = −1.9 (c = 0.03, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 2.1 Hz, 1H), 7.70 (dd, J = 2.1, 8.1 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 4.42 (dd, J = 2.9, 9.8 Hz, 1H), 3.97 (d, J = 2.9, 1H), 3.69 (s, 3H), 1.89−1.79 (m, 2H), 1.67−1.57 (m, 1H), 1.55−1.41 (m, 2H), 0.98−0.86 (m, 6H); 13 C{1H} NMR (100 MHz, CDCl3): δ 168.9, 163.7, 136.6, 135.9, 133.5, 128.8, 127.3, 122.9, 80.7, 52.7, 45.6, 41.6, 21.8, 20.8, 9.8, 9.6; IR (neat): 2959, 2888, 1716, 1601, 1468, 1414, 1255, 1227, 1166, 1130, 987, 907, 767, 638; HRMS (APCI) m/z: [M+ Na]+ Calcd for C16H19BrO4Na 377.0358; Found 377.0361. Methyl 3-(4-Nitrophenyl)-5-oxo-2-(pentan-3-yl)tetrahydrofuran3-carboxylate (cis-56). Prepared according to general procedure B, using freshly distilled 2-ethylbutyraldehyde (53, 30.3 μL, 0.246 mmol) and anhydride 56 (54.4 mg, 0.246 mmol). The reaction was stirred for 13 days to give a diastereomeric mixture of carboxylic acids in a 87:13 ratio (cis:trans). After esterification, the diastereomer cis-56 was isolated and purified by flash column chromatography, eluting with 75:25 hexanes:EtOAc, to give cis-56 as a yellow oil (43.7 mg, 53%, 95% ee). CSP-HPLC analysis: ACQUITY UPC2, Trefoil CEL2, 2.5 μm (3.0 × 150 mm). ABPR: 1500 (psi). A (CO2) = 97%/B (Ethanol/ACN 1:1, v:v) = 3%, 1.2 mL min−1, 30 °C, UV detection at 254 nm, retention times: 3.3 min (minor enantiomer) and 3.8 min (major enantiomer); TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.69; [α]20D = +5.0 (c = 0.01, CHCl3); 1H NMR (400 MHz, CDCl3): δ 8.27 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 5.06 (d, J = 3.4 Hz, 1H), 3.81 (s, 3H), 3.59 (d, J = 17.1 Hz, 1H), 2.72 (d, J = 17.1 Hz, 1H), 1.84−1.76 (m, 1H), 1.55−1.46 (m, 2H), 1.47−1.41 (m, 2H), 1.02−0.93 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 172.8, 171.0, 147.4, 127.2, 124.3, 85.9, 57.9, 53,3, 42.8, 41.6, 23.1, 20.6, 11.2, 11.0; IR (neat): 2962, 2922, 1786, 1722, 1600, 1512, 1409, 1512, 1347, 1233, 1206, 1185, 1012, 949, 853, 798, 703; HRMS (APCI) m/ z: [M + H]+ Calcd for C17H22NO6 336.1441; Found: 336.1438. Methyl 6-Oxo-2-(pentan-3-yl)-4-phenyl-3,6-dihydro-2H-pyran-3carboxylate (cis-58). Prepared according to general procedure D, using freshly distilled 2-ethylbutyraldehyde (53, 30.3 μL, 0.246 mmol). The reaction was stirred for 72 h to give a diastereomeric mixture of carboxylic acids in a 95:5 ratio (cis:trans). After esterification and purification by flash column chromatography, eluting with 80:20 hexanes:EtOAc, cis-58 was isolated as a white solid (41.6 mg, 56%, 89% ee). CSP-HPLC analysis: Chiralcel OD (4.6 mm × 25 cm), hexane/IPA: 90/10, 0.3 mL min−1, RT, UV detection at 254 nm, retention times: 52.7 min (enantiomer) and 55.8 (major enantiomer). Mp 132−134 °C; TLC (hexanes/EtOAc, 8:2 v/v): Rf = 0.5; [α]20D = −3.6 (c = 0.04, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.63−7.54 (m, 2H), 7.48−7.44 (m, 3H), 6.55 (s, 1H), 4.44 (dd, J = 3.1, 9.1 Hz, 1H), 3.93 (d, J = 3.1 Hz, 1H), 3.73 (s, 3H), 1.84−1.69 (m, 3H), 1.70−1.62 (m, 1H), 1.53−1.44 (m, 1H), 0.98−0.94 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.7, 165.0, 152.1, 134.9, 130.9, 129.2, 126.1, 116.8, 79.9, 52.9, 45.2, 41.7, 20.2, 19.7, 9.9, 9.6; IR (neat): 3086, 2965, 2877, 1721, 1696, 1624, 1446, 1353, 1269, 1245, 1086, 1012, 990, 893, 777, 689, 602, 576; HRMS (APCI) m/z: [M + H]+ Calcd for C18H23O4: 303.1590; Found: 303.1598. Methyl 2-Benzhydryl-6-oxo-4-phenyl-3,6-dihydro-2H-pyran-3carboxylate (cis-60). Prepared according to general procedure D, using freshly distilled diphenylacetaldehyde (59, 43.6 μL, 0.246 mmol). The reaction was stirred for 2 days furnishing only the

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02332. Compound cis-33 (CIF) 1 H and 13C NMR spectra, analytical and crystallographic data, and computational study (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Cristina Trujillo: 0000-0001-9178-5146 Stephen J. Connon: 0000-0003-2984-9246 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from Science Foundation Ireland (12/IA/ 1645) is gratefully acknowledged. We are grateful to ICHEC for the provision of computational facilities and to Dr. Goar Sánchez for the AIM graphical outputs.

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REFERENCES

(1) Jayne, H. W.; Jayne, H. W. Ueber das Phenyl-Butyrolacton und die Phenyl-Paraconsäure. Justus Liebigs Ann. Chem. 1883, 216, 97. (2) For earlier related work by Perkin, see: (a) Perkin, W. H. On the Hydride of Aceto-Salicyl. J. Chem. Soc. 1868, 21, 181. (b) Perkin, W. H. On the Formation of Coumarin and of Cinnamic and of other Analogue Acids from the Aromatic Aldehydes. J. Chem. Soc. 1877, 31, 388. (3) (a) Erdmann, H.; Kirchhoff, R. Disubstituirte Naphtaline aus den isomeren Chlorphenylparaconsäuren. Justus Liebigs Ann. Chem. 1888, 247, 366. (b) Erdmann, H.; Schwechten, E. Ueber gechlorte Abkömmlinge des Benzaldehyds. Justus Liebigs Ann. Chem. 1890, 260, 53. (c) Fuson, R. C. Naphthalene and the Centroid Structure. J. Am. Chem. Soc. 1924, 46, 2779. (d) Shoesmith, J. B.; Guthrie, A. The Synthesis of 1-Phenanthrol. J. Chem. Soc. 1928, 0, 2332. (e) Jones, J. B.; Pinder, A. R. Some Synthetical Investigations in Isocoumarin Chemistry. J. Chem. Soc. 1958, 2612. (4) For early work on the imine-based reaction (different mechanism): (a) Castagnoli, N. Condensation of Succinic Anhydride with N-Benzylidene-N-Methylmine. Stereoselective Synthesis of transand cis-1-Methyl-4-Carboxy-5-Phenyl-2-Pyrrolidinone. J. Org. Chem. 1969, 34, 3187. (b) Cushman, M.; Gentry, J.; Dekow, F. W. Condensation of Imines with Homophthalic Anhydrides. A

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The Journal of Organic Chemistry (25) Ö zcan, S.; Balci, M. The Chemistry of Homophthalic Acid: A New Synthetic Strategy for Contruction of Substituted Isocoumarin and Indol Skeletons. Tetrahedron 2008, 64, 5531.

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